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Home , Acrocallosal syndrome, Holoprosencephaly

J Med Genet: first published as 10.1136/jmg.28.5.297 on 1 May 1991. Downloaded from

J3Med Genet 1991; 28: 297-303 297 - ('pseudotrisomy 13') syndrome: a syndrome with features of hydrolethalus and Smith-Lemli-Opitz syndromes. A collaborative multicentre study

A Verloes, S Ayme, D Gambarelli, M Gonzales, M Le Merrer, N Mulliez, N Philip, J Roume

Abstract Case reports A syndrome of holoprosencephaly and postaxial CASE 1 polydactyly, associated with , heart This stillborn girl was delivered at 34 weeks of defect, adrenal hypoplasia, and other visceral gestation. Hydramnios was reported at 51/2 months. malformations, has been observed in five unrelated weight was 1980 g (10th centile), length 43 cm children with normal . Clinical (50th centile), and OFC 34 cm (>90th centile). overlap with lethal acrodysgenital dwarfism (Smith- with proboscis, microstomia, thick dysplastic Lemli-Opitz syndrome type II) and hydrolethalus ears, and postaxial polydactyly of the upper limbs syndrome is discussed. Recessive inheritance were noted. There were no visceral malformations, seems likely. except for atrial septal defect of the ostium secundum type. Microscopic examination of several organs, including pancreas and kidneys, showed them to be normal. The fetal zone of both adrenals was hypo/ Holoprosencephaly and polydactyly are the hallmarks aplastic. The brain was a very small holosphere of 13 and allow a consistent diagnosis in most surrounded by very enlarged subarachnoid spaces. instances. However, isolated cases suggested the The hypophysis was absent. Chromosomal analysis existence of a non-chromosomal syndrome which was normal, 46,XX. The parents were Brazilian; the http://jmg.bmj.com/ mimics, at first glance, the external anomalies of father was 31 and the mother 30. No family data were trisomy 13. Five new observations allow us to available. delineate more accurately this new multiple congenital anomaly syndrome. CASE 2 This hydropic female fetus died in utero at 26 weeks by dates. She weighed 920 g and was 35 cm long. OFCwas not recorded (vaultdislocation). Premaxillary Centre for Human Genetics, Liege University, Pathologie on September 24, 2021 by guest. Protected copyright. B23, CHU Sart-Tilman, B-4000 Liege, Belgium. agenesis, cleft palate, and bilateral postaxial poly- A Verloes dactyly of the upper limbs were present. Visceral malformations included cardiomegaly, D transpo- Centre of and INSERM U242, H6pital sition of the great vessels, a left sided vena cava de la Timone, Marseille, France. flowing into the left atrium, and a large persistent S Ayme, N Philip ductus arteriosus. The oesophagus was narrowed at Department ofPathology, HBpital de la Timone, Marseille, the level of the carina. The gut was malrotated. The France. kidneys and liver were normal but the adrenals were D Gambarelli absent. Tissue lysis prevented accurate examination Department of Embryology and Fetal Pathology, Hopital of the brain. Karyotype was normal, 46,XX. The St Antoine, Paris, France. father was 27 and the mother 22 years old. They were M Gonzales, N Mulliez, J Roume not consanguineous and their karyotypes were Clinique de Genetique Medicale and INSERM U12, normal. The mother had had two previous spontaneous HBpital Necker-Enfants Malades, Paris, France. abortions at 10 and 12 weeks, respectively (not M Le Merrer examined). Correspondence to Dr Verloes. CASE 3 Received for publication 26 April 1990. This male fetus was born at 33 weeks ofgestation after Revised version accepted for publication 27 September 1990. transvaginal decompression of hydrocephalus. J Med Genet: first published as 10.1136/jmg.28.5.297 on 1 May 1991. Downloaded from

298 Verloes, Ayme, Gambarelli, Gonzales, Le Merrer, Mulliez, Philip, Roume

hypoplasia, and x rays showed hemivertebrae at the S2 level. The brain weighed 150 g. The olfactory tracts were absent. Holoprosencephaly was of the semilobar type and hypophysis was present. Micro- scopic examination showed that the kidneys, liver, adrenals, thymus, thyroid, lungs, pancreas, spleen, and testes were normal. The karyotype was normal, 46,XY. He was the first child of non-consanguineous parents and the family history was unremarkable.

CASE 4 Hydrocephalus and holoprosencephaly were suspected on ultrasound in this fetus. An amniocentesis was performed despite oligohydramnios. The fetal karyotype was 46,XY. Acetylcholinesterase electro- phoresis and a fetoprotein level were normal. How- ever, owing to the severity of the hydrocephalus, a termination of was performed at 20 weeks. The fetus weighed 300 g. External anomalies included a median cleft and complete cleft palate, hyper- telorism, a short neck (fig 2), bilateral postaxial polydactyly of both upper and lower limbs, and club feet (fig 3). Necropsy showed incomplete segmen- tation of the lungs, a ventricular septal defect, and F bilateral hypoplastic kidneys. The extremely small brain was explained by alobar holoprosencephaly (fig Figure I 4 b,c,d). The suspected hydrocephalus was in fact an almost empty skull (fig 4a). Gyration was grossly Weight was 1760 g, length 44 cm, and OFC 34 cm. abnormal. The cerebellum and the eyes were normal. Premaxillary hypoplasia with bilateral labiopalatine This fetus was the product of the first pregnancy of a clefts, microphthalmia, bilateral upper limb postaxial young gypsy couple (mother aged 20) with a high http://jmg.bmj.com/ polydactyly, and slight penile hypoplasia were degree of consanguinity (probable brother-sister observed (fig 1). Necropsy showed an endocardial union). With a different partner, the mother had had cushion defect, a left vena cava, abnormal pulmonary another pregnancy two years earlier which ended in a segmentation, aplasia ofthe gall bladder, and testicular stillborn male which was not examined. on September 24, 2021 by guest. Protected copyright.

Figure2 Patient4:facialfeatures. J Med Genet: first published as 10.1136/jmg.28.5.297 on 1 May 1991. Downloaded from

)haly-polydactyly ('pseudotrisomy 13') syndrome 299

Figure 3 Patient4:acral anomalies. http://jmg.bmj.com/

CASE 5 Discussion This stillborn male was born at 31 weeks of gestation. The clinical spectrum of defects seen in these five He was the product of the third pregnancy of an cases is consistent: holoprosencephaly sequence (with unrelated young couple who already had a normal boy its secondary facial consequences), visceral malfor- and who had had a spontaneous abortion. After this mations (mostly heart defects), and polydactyly. It , they had two further , carefully suggests at first glance trisomy 13. monitored by ultrasound, which resulted in the birth on September 24, 2021 by guest. Protected copyright. of two normal boys. During the pregnancy of this case, the mother had salpingitis treated by tetracyclines and prednisone (60 REVIEW OF PUBLISHED REPORTS mg/day) from the third to the tenth week of gestation. Eight previous reports have described the same Polyhydramnios developed at the beginning of the syndrome. In 1986, Lieber et all briefly reported a sixth month, which necessitated several evacuations. stillborn infant with holoprosencephaly, heart defect, Because of a suspicion of hydrocephalus on ultra- male pseudohermaphroditism, and polydactyly. sound, a fetal karyotype was performed at 28 weeks Smith-Lemli-Opitz (SLO) syndrome was the on amniotic cells, which was normal, 46,XY. The suggested diagnosis. In a paper on the possible fetus died spontaneously at 31 weeks and was identity of the SLO and the hypothalamic hamarto- immediately evacuated. It weighed 1800 g (50th blastoma syndrome (HHS), Donnai et a12 reported centile) and showed an absence of ocular globes, a two fetuses with holoprosencephaly, polydactyly, and single nostril, bilateral postaxial polydactyly, and anal stenosis, one of which had male pseudoherma- hypoplastic male external genitalia. Necropsy showed phroditism. In 1987, Young and Madders3 described the presence of a large ventricular septal defect and a stillborn infant with holoprosencephaly, micro- agenesis of the adrenal glands. The diagnosis of phthalmia, hydrocephalus, polydactyly, and a heart was proposed at that time defect as a 'new syndrome'. This paper prompted (1984). several comments: Moerman and Fryns4 reported a J Med Genet: first published as 10.1136/jmg.28.5.297 on 1 May 1991. Downloaded from

300 Verloes, Ayme, Gambarelli, Gonzales, Le Merrer, Mulliez, Philip, Roume

( 1l; Figure 4 Brain pathology (courtesy ofDrD hI Gambarelli). (a) Empty skull with very small brain. (b) Frontal section. (c, d) Macroscopic aspect. http://jmg.bmj.com/

C !it on September 24, 2021 by guest. Protected copyright. stillborn female with holoprosencephaly, hydro- suggested that their fetus had the same disorder as the cephalus, microphthalmia, polydactyly, and adrenal one reported by Young and Madders, and coined the and thyroid hypoplasia, and stated that she had the term 'pseudotrisomy 13'. Bachman et a18 reported on same syndrome as that described by Young and two aborted sibs with holoprosencephaly, hydro- Madders3 and not hydrolethalus syndrome (HLS). cephalus, and polydactyly. They suggested that these Andre et a15 described a boy with cebocephaly, fetuses (as well as that of Young and Madders3 and polydactyly, umbilical hernia, hypospadias with other cases) had HLS. The main clinical features of 16 micropenis, thyroid, adrenal, and testicular hypo- cases are summarised in the table. We excluded the plasia, and ASD. These authors favoured the diagnosis case of Shiota and Tanimura,9 who described a 6 week of HLS. Atkin et aP briefly described two 46,XY sibs old male with holoprosencephaly, tetramelic with ambiguous genitalia and polydactyly: the first polydactyly, and VSD, as chromosomal analysis was one had , hypotelorism, and an imper- not reported. forate anus; the second one had cyclopia, a heart defect, and ambiguous genitalia. The authors excluded SLO. Hewitt et al7 described an 18 week old aborted RATIONALE FOR CLINICAL DELINEATION male fetus with holoprosencephaly, hydrocephalus, We have considered the alternative diagnostic options polydactyly, and an 'asymmetrical' heart. They described in published reports. J Med Genet: first published as 10.1136/jmg.28.5.297 on 1 May 1991. Downloaded from

Holoprosencephaly-polydactyly ('pseudotrisomy 13') syndrome 301 Clinical features in 11 published and five personal cases of holoprosencephaly-polydactyly syndrome. Reference and (case no) 1 2 3 4 5 6 7 8 This report Total (1) (1) (1) (2) (1) (1) (1) (2) (1) (1) (2) (1) (2) (3) (4) (5) 16

Hydramnios ? ?. .. + - - - + 2 Hydrops fetalis ------+ - - - 1 Parental consanguinity ? ------+ + ? - ? + - 3 Age (father) ? 30 ? ? 57 31? 45 ? 31 25 ? ? 26 Mean: 35 Age (mother) ? 25 ? ? 34 31 30 28 29 30 22 ? 20 23 Mean: 27-2 Hydrocephalus ? + - + + ? + + + ? + + + + 10 Holoprosencephaly + PA CE PA ET CE HY CY PA CE + CY PA PA PA CE 16 Cerebellar hypoplasia ? ? ? ? + ? ?? ? + ? ? ? ? ? 2 Antehypophysis aplasia ? ? ? ? + ? ? ? ? ? ? + ? ? ? ? 2 Eye anomaly (excluding microphthalmia) ? ? ? CA RD AN ? ? ? ? ? AN 4 Heart defect + 2 - - 2 - 5 7 ? 2 1,6,8 2,4 3 3 10 Lung malsegmentation ? - ? + - - ? ? - + + 3 Gut malrotation ? - + - - ? ? - ? - + 2 Gall bladder aplasia ? - ? ? - - ? ? - ? ? - + 1 Umbilical hernia ? - - - + - + ? - - 3 Kidney hypoplasia ? - + + - ? ? ? -- ? - - + - 3 Imperforate anus - - + + - - + +.-- - 4 Adrenal hypoplasia ? ? ? + + + ? ? + ? ? + + ? + 7 Thyroid hypoplasia ? ? ? ? + + ??? ? ? ? ? ? ? - 2 Karyotype XY XY XY XX XX XY XY XY XY XY (XY?) XX XX XY XY XY Sex ratio: 12:4 Ambiguous male genitalia + - + - + + 4/12 males Penile hypoplasia + + + + + + ? ?? + - + 8 Hypospadias + - + + + + - - ? + - - 6 Testicular hypoplasia ? - ? + ? ? ?? ? + - + 3 UL postaxial polydactyly + + + + + - + - + + + + + + + + 14 LL postaxial polydactyly - - + - - + - + + + + - + + 8 Club feet ? + + + - - + ...... + - 5 Sacral anomalies + ? ? ? ? ? ? ? ??? ? - + ? - 2 /stillborn ? --- 4/0 - 2/0 - 0/1 1/0 ?=Not mentioned. CA=cataracts. RD=retinal dysplasia. AN=anophthalmia. PA=premaxillary agenesis. CY=cyclopia. ET=ethmocephaly. CE=cebocephaly. HY=hypertelorism. 1=PDA. 2=ASD. 3=VSD. 4=endocardial cushion defect. 5=single ventricle. 6=D transposition. 7='asymmetrical' heart. 8=abnormal venous return. http://jmg.bmj.com/

Lethal acrodysgenital dwarfism (LAD) or Smith-Lemli- male cases showed the typical 'sex reversal', two of Opitz type II whom had 2/3 cutaneous syndactyly of the . Although the clinical heterogeneity of Smith-Lemli- Opitz (SLO) syndrome was suspected for a long time, its severe form was only definitely delineated in 1987 Hydrolethalus syndrome et and in 1988 by Le Merrer et al. l l Over This is a lethal, recessively inherited syndrome by Curry allo on September 24, 2021 by guest. Protected copyright. 50 cases were collected, most ofthem already published reported almost exclusively from Finland.'2 13 It as 'common' SLO, and some with other diagnoses. includes midbrain anomalies (midline cleft with This autosomal recessive syndrome shows specific agenesis of the and ventriculo- facial dysmorphism, severe IUGR, multiple visceral subarachnoid fistula) with severe external hydro- malformations, and sexual ambiguity or sex reversal. cephalus, micropolygyria, key hole shaped foramen Agenesis of the corpus callosum is common but magnum, deep and wide set eyes, facial clefts, neither holoprosencephaly nor imperforate anus has micrognathia, atrioventricular defects, postaxial been reported. Its genetic independence from polydactyly of the upper limbs, 'pathognomonic' 'classical' SLO (type I) is still in dispute. Donnai et a12 preaxial polydactyly (hallux duplex) of the lower established this diagnosis for their two cases. In limbs (sometimes associated with postaxial poly- abstract 1 of Lieber et al,' many features were dactyly), club feet, and laryngotracheopulmonary consistent with the diagnosis of LAD, although IUGR malformations. Polyhydramnios is also a feature. In was absent. SLO and LAD are primarily dysmorphic more than 50 cases of HLS, no holoprosencephaly has syndromes, but holoprosencephaly blurs the typical been reported'3 although olfactory bulbs were absent facial anomalies. Atkin6 excluded the diagnosis of in one case. 12 Taking each case separately, the pheno- LAD for the less affected child of his report, who had type of our patients seems closely related to HLS, only minor facial involvement, but no illustrations but, if we tabulate the features of the 16 cases with were published. Micrognathia was only quoted in holoprosencephaly, the pattern of defects is different. case 1 of Donnai et al.2 Nevertheless, four out of 11 Polydactyly of the feet, when present, is always J Med Genet: first published as 10.1136/jmg.28.5.297 on 1 May 1991. Downloaded from

302 Verloes, Ayme, Gambarelli, Gonzales, Le Merrer, Mulliez, Philip, Roume postaxial, and never associated with hallux duplex true. Nevertheless, diagnosis of trisomy 13 is possible (case 1 of Bachman et al8 had "splayed, broad in a stillborn infant with holoprosencephaly and hallux"), and hydramnios has been noted only twice. polydactyly for which analysis failed Moreover, sexual ambiguity has not been observed in (or was not done). Misleading genetic counselling and HLS, and anterior cleft of the foramen magnum has inappropriate prenatal diagnosis could ensue. Micro- not been reported among the children with holo- dysplasia of the pancreas is considered to be the most prosencephaly. specific histopathological change in trisomy 13.25 Systematic pancreatic sampling could be an advisable policy when the karyotype is not known at the time of '4 15 necropsy. Ectopic splenic tissue has not been observed. This is defined as the association of hypertelorism, Most of the malformations in these syndromes are absent corpus callosum, postaxial polydactyly of the explained by a very early disturbance oforganogenesis hands/feet, and inconstant hallux duplex. It could which begins about the fifth week (Streeter's stages represent an allelic, attenuated form of HLS.16 17 No XIV to XVI). One may hypothesise that at least part reported. ofthe malformation complex observed in LAD, HLS, holoprosencephaly has ever been trisomy 13, and in our patients could be the result of a specific, primitive, genetically determined event that alters the development of the brain and perhaps Hypothalamic hamartoblastoma syndrome of other structures (such as limb bud differentiation). About 24 children have been reported with hypo- This disturbance could induce secondary develop- thalamic hamartoblastoma, antehypophyseal insuffi- mental field defects by either mechanical constraint, ciency, multiple visceral anomalies, and postaxial specific or non-specific biochemical deregulation of polydactyly. In three cases, holoprosencephaly was induction and cellular interactions, or by desyn- present. 1-20 Diagnosis is straightforward at necropsy, chronisation of parallel sequential events. Most of the but can easily be missed on CT scanning. Anyane- malformations observed in the newborn could then be Yeboa et al2l described a child with holoprosencephaly considered as sequence(s), and the homology between and hypothalamic hamartoma as having HLS, but it several syndromes would only reflect a similarity in was more likely to have been affected by hypo- chronology and topography of the primitive event. thalamic hamartoblastoma syndrome. This diagnosis Then, they would lose most of their significance for could not be ruled out in our patient 2. nosology and differential diagnosis. Hypothalamic hamartoblastoma syndrome (HHS) gives some support to this theory: this multiple malformation http://jmg.bmj.com/ Varadi-Papp syndrome (orofaciodigital syndrome type syndrome is associated with a focal tumour of very VI) early onset. Phenotypic expression varies from almost This syndrome was reported in an inbred Hungarian normal children to holoprosencephaly, polydactyly, gypsy family.22 Features included hallux duplex, and multivisceral malformations. Of even greater polydactyly, cleft lip/palate, heart defect, and mental interest are the observations of some features resemb- retardation. Arhinencephaly was reported in some ling HHS associated with apparently non-tumoural grey matter ectopia19 or subarachnoid cysts26 localised cases. A combination of hypoplasia of the vermis, on September 24, 2021 by guest. Protected copyright. lingual tumours, and gingival frenula is patho- in the same area. gnomonic. Based on these considerations, and in the ignorance of the true pathophysiology of these syndromes of multiple congenital anomalies, we suggest (following the opinion of Cohen27) that holoprosencephaly could Grote syndrome be specific enough to justify the delineation of a This unique combination of holoprosencephaly, provisionally 'new' syndrome. tetramelic octodactyly, heart defect, bilateral tibial Accurate incidence is impossible to discover. No agenesis, andmultivisceralmalformations was reported other convincing records were found in our larger in a single family.23 series of fetal/neonatal necropsies which included 5000 records from St Antoine Hospital, Paris, 2100 from Marseille, and 2000 from Liege+Loverval. Trisomy 13 Most surveys on holoprosencephaly were undertaken This chromosomal anomaly should be considered, before the cytogenetic era and no compatible cases are although it is easy to rule out. The common state- quoted in more recent reviews.27134 Underdevelop- ment'4 that trisomy 13 is likely if holoprosencephaly ment of the adrenals or thyroid or both was recorded is associated with many extracephalic manifestations in most cases, which is likely to be explained by some (while chromosomes are more often normal if holo- degree ofhypopituitarism. This should be investigated prosencephaly occurs as an isolated anomaly) remains in further reports. The sex ratio is 12:4. J Med Genet: first published as 10.1136/jmg.28.5.297 on 1 May 1991. Downloaded from

Holoprosencephaly-polydatyly ('pseudotrisomy 13') syndrome 303

INHERITANCE AND GENETIC COUNSELLING 12 Salonen R, Herva R, Norio R. The hydrolethalus syndrome: delineation of a "new" lethal malformation syndrome based on Most cases have been sporadic. Two published cases 28 patients. Clin Genet 1981;19:321-30. and the very close consanguinity of our case 4 are 13 Salonen R, Herva R. Hydrolethalus syndrome. Med Genet strong arguments for an autosomal recessive mode of 1990;27:756-9. 14 Schinzel A, Schmid W. Hallux duplication, postaxial polydactyly, inheritance. Nevertheless, strikingly high parental absence of the corpus callosum, severe mental retardation and ages in several isolated cases could be an argument for additional anomalies in two unrelated patients: a new syndrome. Am Med Genet novo Submicroscopic 1980;6:241-9. de dominant mutation. 15 Philip N, Apicella N, Lassman I, Ayme S, Mattei JF, Giraud F. chromosomal duplication or rearrangement in the The acrocallosal syndrome. EurJ Pediatr 1988;147:206-8. 16 Schinzel A, Kaufmann U. The acrocallosal syndrome in sisters. region extending between 13q31 and 13q34 is an Clin Genet 1986;30:399-405. alternative hypothesis. It should be tested in further 17 Aughton DJ, Cassidy SB. Hydrolethalus syndrome: report of an cases resolution banding and appropriate apparent mild case, literature review, and differential diagnosis. by high AmJ Med Genet 1984;27:935-42. DNA probes. As long as this problem is not resolved, 18 Hall JG, Pallister PD, Clarren SK, et al. Congenital hypothalamic genetic counselling must be carried out very hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly-a new syndrome? Part I: clinical, causal cautiously. and pathogenetic considerations. Am Med Genet 1980;7: We do not recommend the use of 'pseudotrisomy 47-74. 13 syndrome' (suggested by Hewitt etal7 and Cohen27) 19 lafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, Graham JM. Case report and delineation of the congenital hypothalamic to describe this syndrome. This is confusing for a hamartoblastoma syndrome (Pallister-Hall syndrome). Am 7 cytogenetically normal syndrome, and the pathological Med Genet 1989;33:489-99. 20 Verloes A, Gillerot Y, Donnay M, Langhendries JP, Fryns JP, findings are not identical. 'Holoprosencephaly- Koulischer L. Syndromatic hypothalamic hamartoblastoma polydactyly syndrome' appears to be a more neutral (Marcuse-Hall-Pallister syndrome). Another case and critical review of the literature. Am J Med Genet (submitted). term, and summarises the two most salient clinical 21 Anyane-Yeboa K, Collins M, Kupsky W, Malman J, Malin J, features. Yeh M. Hydrolethalus (Salonen-Herva-Norio) syndrome: further clinicopathological delineation. Am Med Genet 1987; 26:899-907. 22 Varadi V, Szabo L, Papp Z. Syndrome of polydactyly, cleft lip/palate or lingual lump, and psychomotor retardation in 1 Lieber E, Valdarama E, Chasalow F. Multiple malformation endogamic gypsies. Med Genet 1980;17:119-22. syndrome suggestive of Smith-Lemli-Opitz syndrome with 23 Grote W, Rehder H, Weisner D, Wiedemann HR. Prenatal holoprosencephaly in a 46,XY still-born infant. Am Hum diagnosis of a probable hereditary syndrome with holopro- Genet 1986;39(suppl):200A. sencephaly, hydrocephaly, octodactyly and cardiac malforma- 2 Donnai D, Burn J, Hughes H. Smith-Lemli-Opitz syndromes: tions. EurJ Pediatr 1984;143:155-7. do they include the Pallister-Hall syndrome? Am Med Genet 24 Burk U. Genetic counselling in holoprosencephaly. Helv Paediatr 1987;28:741-3. Acta 1982;37:231-7. 3 Young ID, Madders DJ. Unknown syndrome: holoprosencephaly, 25 Moerman P, Fryns JP, van der Steen K, Kleczkowska A, congenital heart defects, and polydactyly. Med Genet 1987;24: Lauweryns J. The pathology of trisomy 13 syndrome. Hum 714-6. Genet 1988;80:349-56. http://jmg.bmj.com/ 4 Moerman P, Fryns JP. Holoprosencephaly and postaxial poly- 26 Pallister PD, Hecht F, Herrmann J. 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